PROJECT SUMMARY Alzheimer's disease (AD) is an area of significant unmet need that creates a national burden of ~$259 billion annually. AD is the leading cause of dementia, affecting 10% of Americans over the age of 65. Demographic shifts and the age-related nature of AD will soon place this disease as the costliest health care expenditure in the U.S. with a projected impact of $1.1 trillion per year by 2050. Current therapies target secondary aspects of the disease to temporarily and modestly ease symptoms; there no FDA-approved therapies that slow progression or cure the disease. According to the Alzheimer's Association, ?a breakthrough drug would treat the underlying disease and stop or delay the cell damage that eventually leads to the worsening of symptoms.? The first disease-modifying neuroprotective therapeutic will clearly represent a global medical innovation. Astrocyte Pharmaceuticals Inc. is developing a small molecule, AST-004, for acute brain injury patients. The proprietary approach at Astrocyte Pharmaceuticals differs significantly from historical neuron-centric neuroprotective attempts by focusing on a non-neuronal cell type, the astrocyte. Astrocytes have only recently received broader attention as an important cellular target for successful therapeutic research. The protective pathways activated by AST-004 are conserved in ex vivo human brain tissue. AST-004 has demonstrated significant neuroprotective efficacy in various acute animal models of ischemic stroke and traumatic brain injury. AST-004 has a favorable pharmaceutical profile that is amenable to chronic treatment of CNS diseases such as AD. Preliminary data show that AST-004 treatment also increases astrocyte and neuronal viability in a mouse model of AD. This Phase I STTR proposal will (1) define the neuroprotective efficacy of AST-004 in two mouse models of AD and (2) validate the neuroprotective efficacy of AST-004 in highly relevant fresh cortical brain samples from human AD patients. The overall goal of this AST-004 development project is to slow the onset and severity of AD-caused neurodegeneration.